Screening for High Blood Cholesterol

 
Recommendation:
 
Periodic measurement of total serum cholesterol is most 
important for middle-aged men, and it may also be 
clinically prudent in young men, women, and the elderly 
(see Clinical Intervention). All patients should receive 
periodic counseling regarding dietary intake of fat 
(especially saturated fat) and cholesterol (see Chapter 
50).
 

Burden of Suffering
 
High blood cholesterol, cigarette smoking, and hypertension 
are the principal modifiable risk factors for coronary 
artery disease (CAD), the leading cause of death in the 
United States.1 About 1.5 million myocardial infarctions 
(MIs) and over 520,000 deaths from ischemic heart disease 
occur each year in the United States.1,2 These cardiac 
events often occur without warning in persons with no 
previous history of angina pectoris or other clinical 
symptoms. The 30-day case-fatality rate for persons in whom 
MI is the initial manifestation of CAD is about 30%.3 CAD 
is also associated with significant morbidity; the 
discomfort and exertional restrictions of angina pectoris 
and MI can limit productivity, functional independence, and 
quality of life. Cardiovascular diseases cost the United 
States about $80 billion each year.2
 
Efficacy of Screening Test
 
The principal screening test for high blood cholesterol is 
the measurement of total serum cholesterol in specimens 
obtained by either venipuncture or finger-stick. Due to 
biological variation and measurement error, such 
measurements may not always reflect the patient's true 
cholesterol level. Serum cholesterol levels normally 
undergo substantial physiologic fluctuations related to 
gender, stress, and season,4 and therefore a single blood 
test may not always be representative. Repeated 
measurements on the same individual have a standard 
deviation of about 18 mg/dL (0.45 mmol/L), so that the 95% 
confidence interval for a typical adult whose blood 
cholesterol is 220 mg/dL (5.70 mmol/L) would be ;pm36 mg/dL 
(0.95 mmol/L), or 184-256 mg/dL (4.75-6.65 mmol/L).5,6 Due 
to this variation, a single cholesterol measurement should 
not be relied on and the average of multiple tests should 
be used for therapeutic decisions.
 
In addition to biological variation, different laboratory 
instruments for measuring serum cholesterol are subject to 
systematic bias and random sources of error.7 A number of 
instruments in routine use consistently overestimate 
(positive bias) or underestimate (negative bias) the true 
cholesterol value by about 2-7%.4,7-11 More extreme errors 
have also been reported. One study found that a serum 
cholesterol concentration of 250 mg/dL (6.45 mmol/L) was 
reported by one instrument as 285 mg/dL (7.35 mmol/L) (14% 
positive bias) and by another as 301 mg/dL (7.80 mmol/L) 
(20% positive bias).4 Nearly half of all laboratory 
cholesterol results vary by 5% or more from the correct 
value.12 Another potential source of error is poor 
precision (e.g., producing different results on the same 
specimen), although it is generally less of a problem than 
bias.12 This accounts for about 3-4% of variation in the 
results of conventional clinical laboratory equipment5,10 
and desk-top office analyzers.7,13-16 There is also 
significant variation between clinical laboratories (about 
6%) and within individual laboratories (about 3.5%).12
 
Capillary sample measurements are often less accurate than 
analyses of venipuncture specimens. Inadequate training and 
the use of improper techniques in operating the equipment 
can introduce additional sources of error.16 This is 
especially important in relation to desk-top chemical 
analyzers.12 Further research is needed to fully evaluate 
these devices, and programs should be developed to assure 
acceptable performance standards before desk-top 
instruments are recommended for widespread screening.12
 
Since clinical decisions regarding treatment are affected 
by the report of a cholesterol level above a desirable'' 
level, there are potentially important clinical 
consequences resulting from laboratory underestimation or 
overestimation of the actual cholesterol level. Persons 
with high blood cholesterol requiring intervention may be 
advised incorrectly that their serum lipid levels are in 
the desirable range and thus not be retested for some time. 
Conversely, persons who receive falsely elevated test 
results may undergo the inconvenience and cost of follow-up 
testing. In some cases, erroneous cholesterol test results 
may generate unnecessary office visits to health care 
providers. Some patients may experience anxiety and the 
effects of labeling that have been observed in hypertension 
screening, such as absenteeism and psychological 
symptoms.17 Finally, patients receiving inadequate 
follow-up testing may be exposed unnecessarily to treatment 
with cholesterol-lowering drugs.
 
To minimize the adverse effects of misclassification 
resulting from biological variance or laboratory error, an 
average of at least two blood test results is often 
recommended to provide a more accurate measure of the true 
concentration of total cholesterol; three tests are 
recommended if the difference between the first two tests 
is greater than 30 mg/dL [0.80 mmol/L].18 In addition, 
rigorous standards for improving accuracy and precision in 
clinical laboratories are being developed and implemented 
by the College of American Pathologists, the Centers for 
Disease Control, and the National Cholesterol Coordinating 
Committee Laboratory Standardization Panel.12,19 These 
groups have proposed the goal of improving standards for 
accuracy and precision in clinical laboratory measurement 
from the current range of ;pm5% to less than 3% by 1992.
 
Effectiveness of Early Detection
 
Early detection of high blood cholesterol in asymptomatic 
persons allows identification of an important modifiable 
risk factor for CAD. A large body of evidence gathered over 
several decades, including epidemiologic, pathologic, 
animal, genetic, and metabolic studies, supports the lipid 
hypothesis,'' the causal relationship between serum 
cholesterol levels and the development of coronary 
atherosclerosis.20-23
 
The question of whether the lowering of serum cholesterol 
can achieve a significant reduction in the incidence of CAD 
in asymptomatic persons has been of major clinical 
interest. Early efforts to answer this question involved 
controlled clinical trials in which asymptomatic 
middle-aged men with selected cardiac risk factors were 
given low-fat or modified-fat diets.24-32 Such diets 
lowered serum cholesterol levels by about 10-15%, and in 
most trials, this was associated with a reduction in the 
incidence of cardiac events (e.g., myocardial 
infarc-24,25,28-30,32 These early studies, however, 
suffered from a variety of design limitations, such as 
small sample size, selection bias in the recruitment of 
study groups and controls, confounding variables, 
inappropriate statistical analyses, and limited 
generalizability.33,34 Probably due to inadequate sample 
size, most of these studies did not find a significant 
difference in either CAD or overall mortality between 
intervention and control groups.24-27
 
The ability of cholesterol-lowering drugs to reduce the 
incidence of CAD in asymptomatic persons has been 
demonstrated in three well-designed randomized controlled 
trials involving asymptomatic middle-aged men with high 
blood cholesterol. In the WHO Cooperative Trial, which 
involved over 15,000 men, subjects receiving clofibrate 
experienced a statistically significant 20% reduction in 
the overall rate of MI and 25% reduction in nonfatal MI 
when compared with controls receiving olive oil 
capsules.35-37 The incidence of fatal MI was similar in 
both groups. The Lipid Research Clinics (LRC) Coronary 
Primary Prevention Trial, a multicenter study of 
cholestyramine involving 3806 men, reported an incidence of 
cardiac events of 7.0% in persons receiving cholestyramine 
and 8.6% in those receiving placebo.38-42 This 19% 
reduction in the incidence of CAD was also statistically 
significant. Nonfatal MI and CAD mortality were 19% and 24% 
lower, respectively, in the group taking cholestyramine, 
and the incidence of angina, positive exercise tests, and 
coronary bypass surgery was also reduced. The Helsinki 
Heart Study, a trial involving 4081 asymptomatic men, 
reported a statistically significant 34% reduction in the 
incidence of cardiac events (nonfatal MI and cardiac death) 
in men receiving gemfibrozil.43
 
Taken together, these studies provide compelling evidence 
that the incidence of nonfatal MI and fatal cardiac disease 
can be reduced by lowering serum cholesterol. The 
randomized controlled trials that provide the strongest 
evidence, however, used drugs rather than diet to achieve 
this effect and involved a select population group, 
primarily white men aged 35-59 with serum cholesterol 
values above 255-265 mg/dL (6.60-6.85 mmol/L).38,43 A 
current focus of interest is the extent to which this 
evidence is generalizable to other population groups (i.e., 
women, young men, the elderly, persons with less marked 
elevation of serum cholesterol) or to dietary measures.
 
Women, young men, and the elderly presumably benefit to 
some extent from lowering serum cholesterol. There are 
uncertainties, however, regarding the magnitude of benefit 
from screening these populations since elevated blood 
cholesterol is either a weaker risk factor or a less common 
abnormality in these34,44-47 Persons with borderline high 
cholesterol (200-240 mg/dL [5.15-6.20 mmol/L]), lacking the 
high blood cholesterol levels required of participants in 
the above trials, may benefit less by lowering cholesterol. 
A cohort study involving over 350,000 men48,49 and 30-year 
longitudinal data from the Framingham Study50 provide 
evidence that CAD risk increases in a continuous and graded 
fashion beginning with serum cholesterol levels as low as 
180 mg/dL (4.65 mmol/L).51 The risk rises sharply above 
220-240 mg/dL (5.70-6.20 mmol/L), reaching a fourfold 
increase for levels above 260 mg/dL (6.70 mmol/L), which is 
the 90th percentile of middle-aged men. It follows that 
reductions in persons with borderline high cholesterol 
would be of less substantial benefit than for persons with 
severe elevations; a 50 mg/dL (1.30 mmol/L) reduction 
lowers absolute risk by about 50% in persons with a serum 
cholesterol of 300 mg/dL (7.75 mmol/L) but only by 25% at a 
level of 250 mg/dL (6.45 mmol/L) and only 7.5% at 200 mg/dL 
(5.15 mmol/L).22
 
Cardiac risk factors other than high blood cholesterol are 
also important determinants of the benefits that can be 
expected from lowering blood cholesterol. Persons at 
increased risk for CAD because of a history of MI or 
angina, or asymptomatic persons with other cardiac risk 
factors, are thought to experience a greater reduction in 
risk for any given reduction in blood cholesterol than 
persons without these risk factors.18,52 These risk factors 
include male sex, family history of premature CAD, 
cigarette smoking, hypertension, low high-density 
lipoprotein (HDL) cholesterol (less than 35 mg/dL [0.90 
mmol/L]), diabetes mellitus, cerebrovascular or peripheral 
vascular disease, and severe obesity.
 
Another question concerns the magnitude of benefit 
associated with dietary measures. Animal studies, 
epidemiological data, and metabolic research support a 
beneficial effect from diets low in fat, primarily 
saturated fat. Clinical trials in which diet was the sole 
intervention have provided encouraging but not conclusive 
evidence of a significant reduction in the incidence of 
CAD.21,22,44,53,54 The lack of conclusive evidence is due 
at least in part to design limitations (see above). It is 
reasonable to extrapolate from the drug trial findings that 
dietary restrictions, if successful in achieving 
significant reductions in serum cholesterol, can also lower 
the risk of CAD. Meta-analyses and other reviews of data 
pooled from dietary trials suggest that the dose-response 
relationship between dietary reduction of serum cholesterol 
and the risk of CAD is similar to that observed in data 
analyzed from drug trials.55
 
The ability of patients to achieve and maintain reductions 
in dietary fat is still under study. Low-fat diets that 
have been shown in experimental research to achieve 
significant reductions in serum cholesterol may not be 
adopted as readily by all members of the general 
population.34,56 Thus, the more modest reductions in serum 
cholesterol level that result from ordinary fat-controlled 
diets may produce only modest reductions in CAD. 
Nonetheless, when compared with pharmacologic regimens to 
lower serum cholesterol, dietary measures are safer, less 
expensive, and may obviate the need for prescribing 
cholesterol-lowering drugs.
 
In summary, the magnitude of benefit of detecting high 
blood cholesterol may be reduced in women, young men, and 
the elderly; persons with borderline high cholesterol; and 
persons who use dietary measures that do not lower serum 
cholesterol significantly. Lowering serum cholesterol in 
low-risk populations may result in only minor changes in 
population-wide life expectancy.47 On the other hand, 
low-risk individuals account for a large proportion of the 
population. It has been argued from a public health 
perspective that even modest benefits multiplied across 
large numbers of individuals can have significant public 
health implications.57 Even a modest 5% reduction in the 
incidence of CAD would prevent about 75,000 MIs each year 
in the United States.2
 
It is also important to consider the potential health risks 
associated with lowering serum cholesterol. Long-term use 
of cholesterol-lowering drugs, such as nicotinic acid, 
clofibrate, and cholestyramine, is associated with a number 
of unpleasant and potentially serious side effects.22,58,59 
New classes of lipid-lowering drugs, such as lovastatin, 
also have adverse effects60 and have not been in use for 
sufficient time to establish their long-term safety. The 
three major clinical trials involving lipid-lowering drugs 
each reported an increase in non-CAD deaths in intervention 
groups. An increase in violent deaths (accidents, suicide, 
homicide) reported in two of the three trials was not 
statistically significant and was attributed to chance by 
the investigators,38,43 but the findings have raised 
concern among others.61 The third trial reported a 
statistically significant 44% increase in all-cause 
mortality in men taking clofibrate.35-37 Because clofibrate 
also causes gallstones,35 its use for lowering cholesterol 
to prevent CAD is no longer recommended. Studies have 
reported associations between decreased levels of serum 
cholesterol and cancer24,62-65 and gastrointestinal 
disease.24,35,43 Evidence from a large longitudinal study, 
however, indicates that the association with cancer may 
represent an effect of preclinical cancer on blood 
cholesterol rather than an effect of low cholesterol on the 
development of the disease.66 An increased incidence of 
cancer was also not apparent in the three drug trials 
discussed above.
 
Cholesterol screening during childhood has received 
increased attention in recent years. The detection of high 
blood cholesterol during childhood is of potential value in 
identifying those children who are at increased risk for 
developing CAD as adults and who might benefit from more 
intensive dietary interventions and follow-up than would be 
offered in the course of routine well-child care. Studies 
have shown that children with increased intake of dietary 
fat and cholesterol are at increased risk of having high 
blood cholesterol,67 and children with high blood 
cholesterol are more likely than other children to have 
elevated cholesterol levels as adults.68 Dietary habits 
learned in childhood may persist into adult life, and 
parents of children with high cholesterol levels are more 
likely to experience CAD.69 High blood cholesterol may 
produce early atherosclerotic changes before adulthood; 
postmortem studies have demonstrated fatty streaks lining 
the aortas of children and adolescents with high blood 
cholesterol levels.70 Autopsy studies have also noted 
evidence of CAD in adolescent and young adult war 
casualties.71 It is unclear how strongly these pathologic 
changes are associated with subsequent CAD, however. A 
relationship between lowering cholesterol during childhood 
and decreased incidence of CAD during later life has yet to 
be demonstrated in controlled studies, in part due to the 
difficulty of performing such studies. This lack of 
evidence is of concern because it is currently unclear 
whether a policy of routine cholesterol screening of the 
50-60 million children72 in the United States would achieve 
sufficient clinical benefit in later years to justify the 
costs and potential adverse effects of widespread testing. 
Due to the low prevalence of high blood cholesterol in 
children, routine screening is likely to generate a large 
proportion of false positives. There is little information 
on the potential psychological effects on children of being 
labeled'' as having high blood cholesterol. Also, some 
pediatricians have expressed concern that dietary 
restrictions during childhood may affect the child's source 
of calories, calcium, and iron.73 The issue is still under 
active study.
 
Recommendations of Others
 
The National Heart, Lung, and Blood Institute has issued 
recommendations on cholesterol screening in the clinical 
setting in the report of the Expert Panel on Detection, 
Evaluation, and Treatment of High Blood Cholesterol in 
Adults.18 These recommendations were endorsed by the 
National Cholesterol Coordinating Committee, which includes 
representatives from the leading national medical 
organizations. The report recommends routine measurement of 
nonfasting serum cholesterol in all adults aged 20 and 
above at least once every five years and provides a 
detailed protocol to guide follow-up of test results. The 
protocol sets a lower treatment threshold for persons with 
CAD or who are at high risk for CAD and recommends 
averaging two to three separate measurements of total 
cholesterol and low-density lipoprotein (LDL) cholesterol 
to help guide drug treatment decisions. Specific 
recommendations to improve the effectiveness of public 
screening for high blood cholesterol have been issued 
through a workshop sponsored by the National Heart, Lung, 
and Blood Institute.74 The American Academy of Pediatrics 
recommends regular elective testing for high blood 
cholesterol only for children over age 2 who have a family 
history of hyperlipidemia or early MI.75 Others have 
recently recommended universal cholesterol screening for 
all children.76 Recommendations on public screening outside 
the medical setting are currently being prepared by the 
National Cholesterol Coordinating Committee.
 
Discussion
 
Serum cholesterol testing of adults in the United States 
has the potential of achieving a significant reduction in 
the nationwide incidence of CAD. Care is, however, required 
for any program targeting more than 150 million people72 
for testing and follow-up to guard against unnecessary 
health care expenditures and adverse personal consequences. 
In particular, the use of inaccurate laboratory or desk-top 
instruments for screening can lead to large numbers of both 
false-negative and false-positive results. The former can 
delay needed clinical intervention and the latter can lead 
to considerable inconvenience, costs, and adverse 
psychological and medical consequences in persons not 
needing intervention. It is therefore important for 
clinicians to exercise discretion in selecting accurate and 
reliable methods of obtaining blood specimens in the 
clinical setting, to use clinical laboratories that adhere 
to accepted standards of quality control, and to properly 
design treatment strategies based on results confirmed by 
repeated tests.
 
Discretion is especially important in the use of 
cholesterol-lowering drugs. The efficacy of such drugs in 
preventing CAD has been demonstrated most convincingly in 
middle-aged men with serum cholesterol levels above 255-265 
mg/dL (6.60-6.85 mmol/L).38,43 The effect on CAD of using 
lipid-lowering drugs in young men, women, or elderly 
persons, or in those with only mild to moderate elevations 
in blood cholesterol, has not been studied in clinical 
trials of asymptomatic persons. It is therefore reasonable 
to limit the exposure of low- or moderate-risk individuals 
to the unpleasant side effects of lipid-lowering drugs, the 
inconvenience of daily, long-term administration, and the 
potential health risks of agents for which long-term safety 
has yet to be established. There are also economic 
implications to prescribing lipid-lowering drugs in light 
of their expense and the quantities required for long-term 
therapy. Some studies examining the economic benefits of 
preventing CAD have questioned the cost-effectiveness of 
routine drug therapy for elevations in blood 
cholesterol.77-80
 
It has been shown that a low level of HDL cholesterol is an 
independent predictor of CAD. Persons whose HDL cholesterol 
level is at the 20th percentile have two to four times the 
risk of developing CAD as persons whose level is at the 
80th percentile.81,82 Lipid-fractionation studies, which 
enable the calculation of HDL and LDL levels, can therefore 
provide more meaningful information on CAD risk and the 
effectiveness of therapy than can total cholesterol 
measurement. Concerns that total blood cholesterol 
measurements may fail to detect persons at increased risk 
due to low HDL cholesterol (despite a normal total 
cholesterol level) have led to recent recommendations to 
perform lipoprotein analysis routinely on all persons with 
borderline or high total blood cholesterol.83
 
There are substantial economic considerations in the 
performance of fractionation studies as a routine follow-up 
to finding elevated total cholesterol. For example, 
examining lipid profiles on all adults with high blood 
cholesterol (240 mg/dL [6.20 mmol/L] or greater) would 
require performing a $20-$40 test on nearly one-quarter of 
the 150 million adults in the United States.72,84 Although 
it is likely that the information would be useful to 
clinicians, further research is necessary to determine the 
exact prevalence of low HDL cholesterol, the efficacy of 
measures to raise HDL cholesterol, and whether the added 
information provided by routine lipoprotein analysis 
results in an overall improvement in clinical outcome. 
Until this evidence becomes available, lipid fractionation 
studies may be best reserved for the smaller group of 
persons for whom the information is most important, such as 
those being considered for drug therapy and those being 
monitored for response to treatment with 
cholesterol-lowering drugs.
 
Clinical Intervention
 
All patients should receive periodic counseling regarding 
dietary intake of fat (especially saturated fat) and 
cholesterol (see Chapter 50). Periodic measurement of total 
serum cholesterol (nonfasting) is most important for 
middle-aged men, and it may also be clinically prudent in 
young men, women, and the elderly. The optimal frequency 
for cholesterol measurement in asymptomatic persons has not 
been determined on the basis of scientific evidence and is 
left to clinical discretion; an interval of every five 
years (and more frequently for persons with previous 
evidence of elevated cholesterol) has been recommended on 
the basis of expert opinion.18 Cholesterol tests should be 
performed on venous blood samples analyzed by an accredited 
laboratory that meets current standards of accuracy and 
reliability. Abnormal results should be confirmed by a 
second measurement of nonfasting total cholesterol, and the 
mean of both results should be used for subsequent 
therapeutic decisionmaking.
 
All adults with high blood cholesterol (at or above 240 
mg/dL [6.20 mmol/L]) and those persons with borderline high 
cholesterol (200-239 mg/dL [5.15-6.15 mmol/L]) who have 
known CAD or two or more cardiac risk factors should 
receive information about the meaning of results, intensive 
dietary counseling, and follow-up evaluation. The most 
important cardiac risk factors to be considered include 
male gender, premature CAD in a first-degree relative, 
smoking, hypertension, serum HDL cholesterol less than 35 
mg/dL (0.90 mmol/L) (when this information is available), 
diabetes mellitus, previous stroke or peripheral vascular 
disease, and severe obesity. The recommended two-step 
dietary program to lower serum cholesterol has been 
described in detail elsewhere.18 The primary objective of 
the Step-One diet is to reduce all dietary fat intake to 
less than 30% of total calories (with saturated fat 
contributing less than 10% of total calories) and to reduce 
dietary cholesterol intake to less than 300 mg/day. The 
Step-Two diet, which is recommended if the goals of therapy 
are not achieved after three months, differs from the first 
by further restricting intake of saturated fats (to 7% of 
total calories) and dietary cholesterol (200 mg/day).
 
Cholesterol-lowering drugs should be considered in 
middle-aged men in whom blood cholesterol remains 
significantly elevated after a thorough six-month trial of 
dietary intervention.  A suggested threshold for drug 
treatment is 240 mg/dL (6.20 mmol/L) or greater in persons 
with CAD or at least two cardiac risk factors and 265 mg/dL 
(6.85 mmol/L) or greater in persons without risk factors.  
The patient should receive information on the potential 
benefits and risks of long-term therapy before beginning 
treatment on cholesterol-lowering drugs.  It is clinically 
prudent to perform lipid fractionation studies on persons 
being considered for drug treatment and those being 
monitored for response to drug therapy over time.  

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